Title: Dissecting the impact of clonal hematopoiesis on atherosclerosis using multi-scale ?omics Description: Despite current risk prediction, prevention, and therapeutic strategies, coronary artery disease (CAD) continues to remain the leading cause of death in the US and worldwide. I aim to investigate a novel mechanism contributing towards CAD: age-related somatic mutations in bone marrow hematopoietic stem cells predisposing to clonal hematopoiesis (clonal hematopoiesis of indeterminate potential, CHIP). CHIP-related somatic mutations in peripheral blood cells, typically in DNMT3A, TET2, JAK2, and ASXL1, increase risk of CAD by 2-4 fold, independent of other cardiovascular risk factors and similar in magnitude to risk conferred from traditional risk factors. Hematologic knock-out of one of these CHIP driver genes, Tet2, in mice causes larger atherosclerotic lesions. Transcriptomics of cultured bone-marrow-derived macrophages from these mice show significant changes in expression among genes in inflammatory pathways (ex: cytokines/chemokines and phagocytic lysosomal function). CHIP carriers with somatic variants in TET2 have significantly reduced major adverse cardiovascular events when treated with canakinumab, an IL-1B antibody, suggesting that specific therapeutic strategies may be especially influential in CHIP carriers. My overall hypothesis is that whole genome sequencing (WGS) will identify germline genetic variants influencing CHIP carrier state that causally affect atherosclerosis, that transcriptomic analyses in human monocytes will discover biological pathways influenced by CHIP, and that combining germline and somatic data will uncover protective germline genetic variants that may be leveraged towards future therapeutic targets. Specific aims: By integrating germline whole genome sequencing data with somatic variant calls, transcriptomics, cardiac imaging, and clinical data from over 107,000 individuals from the NHLBI Trans-Omics for Precision Medicine consortium, I aim to improve understanding of the mechanistic link between CHIP and atherosclerosis. In aim 1, I will associate germline genetic predisposition to CHIP with coronary artery calcium levels from cardiac CT, and with CAD. This will assess whether CHIP carrier state causally influences subclinical atherosclerosis and clinical atherosclerosis. In aim 2, I will discover the biological networks influenced by CHIP using transcriptomics from human monocytes. In aim 3, I will characterize how germline genetic factors interact with CHIP somatic variants to influence the progression of CHIP to CAD.